Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
J Alzheimers Dis. 2012;28(3):579-92. doi: 10.3233/JAD-2011-111328.
Chronic stress has been suggested to influence the pathogenesis of Alzheimer's disease (AD); however, the mechanism underlying this influence remains unknown. In this study, we created a triple transgenic mouse model that overexpresses corticotrophin-releasing factor (CRF) and human amyloid-β protein precursor (AβPP), to investigate whether increases in the expression of CRF can mimic the effects of stress on amyloid metabolism and the neurodegeneration. Tg2576 mice that overexpresses human AβPP gene were crossbreed with Tetop-CRF (CRF) mice and CaMKII-tTA (tTA) mice to create a novel triple transgenic mouse model that conditioned overexpresses CRF in forebrain and overexpresses human AβPP (called AβPP+/CRF+/tTA+, or TT mice). Then we evaluated serial neuro-anatomical and behavioral phenotypes on TT mice using histological, biochemical, and behavioral assays. TT mice showed a Cushingoid-like phenotype starting at 3 months of age. At 6 months of age, these mice demonstrated increases in tissue-soluble amyloid-β (Aβ) and Aβ plaques in the cortex and hippocampus, as compared to control mice. Moreover, TT mice characterized substantial decreases in dendritic branching and dendritic spine density in pyramidal neurons in layer 4 of the frontal cortex and CA1 of the hippocampus. Finally, TT mice showed significantly impaired working memory and contextual memory, with a modest increase in anxiety-like behavior. Our results suggested genetic increases in the brain of CRF expression mimicked chronic stress on the effects of amyloid deposition, neurodegeneration, and behavioral deficits. The novel transgenic mouse model will provide a unique tool to further investigate the mechanisms between stress and AD.
慢性应激被认为会影响阿尔茨海默病（AD）的发病机制；然而，这种影响的机制尚不清楚。在这项研究中，我们创建了一种三重转基因小鼠模型，该模型过度表达促肾上腺皮质释放因子（CRF）和人淀粉样前体蛋白（AβPP），以研究 CRF 表达的增加是否可以模拟应激对淀粉样代谢和神经退行性变的影响。过度表达人 AβPP 基因的 Tg2576 小鼠与 Tetop-CRF（CRF）小鼠和 CaMKII-tTA（tTA）小鼠杂交，创建了一种新型三重转基因小鼠模型，该模型在前脑中条件性过度表达 CRF 并过度表达人 AβPP（称为 AβPP+/CRF+/tTA+，或 TT 小鼠）。然后，我们使用组织学、生化和行为测定法评估 TT 小鼠的一系列神经解剖和行为表型。TT 小鼠从 3 个月大开始表现出库欣样表型。在 6 个月大时，与对照小鼠相比，这些小鼠的皮质和海马中的组织可溶性淀粉样β（Aβ）和 Aβ 斑块增加。此外，TT 小鼠在前额皮质 4 层和海马 CA1 的锥体神经元中表现出树突分支和树突棘密度显著减少。最后，TT 小鼠表现出明显的工作记忆和情境记忆受损，同时焦虑样行为略有增加。我们的研究结果表明，脑内 CRF 表达的遗传增加模拟了慢性应激对淀粉样沉积、神经退行性变和行为缺陷的影响。这种新型转基因小鼠模型将为进一步研究应激与 AD 之间的机制提供独特的工具。
